Inflammatory demyelinating disease of the central nervous system (CNS) in most cases is a chronic, incurable illness. Manifestations include, but are not limited to, inflammation, axonal degeneration, fatigue, cognitive impairment, neurological impairment and, of course, demyelination. The manifestations may include the following clinical patterns: acute, chronic, single episode, recurrent episodes, progressive, progressive-relapsing, relapsing-progressive, or unremitting.
In most cases such illnesses meet the definition of multiple sclerosis (MS), a pathologically diverse syndrome. No single etiological factor can be demonstrated for MS, but it is widely felt to be an immune-mediated or autoimmune condition resulting from an initial infection with a pathogen, and resulting in a unique and pathological host response directed against antigens within the CNS. By “multiple sclerosis” the present inventor means the commonly observed symptoms of multiple sclerosis.
Multiple sclerosis is a crippling disease that affects over 250,000 Americans. MS is characterized by axonal deterioration in the central nervous system with the associated loss of the insulating myelin sheath from around the axons of the nerve cells. This loss of myelin results in loss of electrical insulation and the “short-circuiting” of the electrical pathways mediated by the affected nerves and progressive neurological impairment. MS usually affects young adults in what should be the healthiest, most productive years of their lives and affects women more often than men.
The symptoms of MS include pain and tingling in the arms and legs; localized and generalized numbness, muscle spasm and weakness; bowel and bladder dysfunction; difficulty with balance when walking or standing; and fatigue. In most cases, people afflicted with MS lose the ability to stand and/or walk entirely. Optic neuritis may occur episodically throughout the course of the disease. The symptoms are exacerbated by viral infection, physical fatigue or emotional stress.
Heretofore, such diseases have been treated by powerful anti-inflammatory agents such as megadose corticosteroids (methylprednisolone) and cytotoxic chemotherapeutic agents (cyclophosphamide, methotrexate, and mitoxantrone). Clinically useful immunomodulatory agents have been identified which are effective in ameliorating multiple sclerosis but not remitting disability. The previously identified immunomodulators include type 1 interferons (largely interferon beta congeners) and glatiramer acetate (a random polymer of amino acids). All these agents decrease inflammatory activity in the central nervous system, which is believed to be the basis for therapeutic effect in altering the disease course. Each of these treatments produces an effectiveness in clinical endpoints of 30-50% decreases in disease relapses, progressive disability, but more effective outcomes occur with magnetic resonance imaging (MRI) based parameters. Currently available treatments are not believed to be effective at reducing pre-existing disability.
Colony stimulating factors are polypeptide agents of various families classified by their action on hematopoetic cell lineages. They are often species specific in their action. They have principally been used to stimulate proliferation of certain lineages. Granulocyte macrophage colony stimulating factor, for example, stimulates proliferation of the stem cells which generate neutrophils and macrophages. Analogous colony stimulating factors may stimulate specific other lineages.
Clinical use of colony stimulating factors (CSFS) has been mostly limited to diseases outside the central nervous system. These molecules have widely been used as mitogens to harvest bone marrow cells, stimulate bone marrow recovery, and treat leukopenia acutely and chronically. Granulocyte-macrophage colony stimulating factor (GM-CSF) has these actions, as well as the ability to increase antigen presentation via upregulation of class II major histocompatibility complex, increase activation of phagocytes, release of proinflammatory cytokines (interleukin-6, interferon-gamma, and tumor necrosis factor), and increase presentation of costimulatory ligands on leukocytes. These actions could be termed pro-inflammatory actions.
Because of the pro-inflammatory actions of GM-CSF, attempts have been made with stimulating anti-tumor immunity with various congeners, including sargramostim, a Saccharomyces-derived recombinant GM-CSF receptor ligand. These efforts have demonstrated long-term safety of administration and limited clinical efficacy in neoplastic disease.
It would seem counterintuitive that an agent which stimulates both innate and specific humoral and cellular immunity should produce an acceptable outcome for an immune-mediated disease such as multiple sclerosis and related CNS demyelinating diseases. A previous and widely cited phase I clinical trial found that interferon-gamma, a proinflammatory cytokine, increased symptoms of multiple sclerosis and was felt to be unsuitable for further investigation. In support of a possible benefit of pro-inflammatory cytokines, studies in rodent models of MS demonstrate that tumor necrosis factor, interferon-gamma and interleukin-6 can cure or ameliorate disease.
The present inventor is the first to establish the benefits of GM-CSF and related colony stimulating factors with respect to treating idiopathic or viral demyelinating or inflammatory diseases of the CNS from either human studies or animal models.